Acupuncture is an ancient (over 2500 years old) therapeutic practice that originated in China and is growing in popularity in the West. However, scientific research into its underlying basic mechanisms is relatively recent and incomplete. The purpose of the proposed Project is to determine how acupuncture, with its variable treatment locations and stimulation techniques, affects human brain activity. We will accomplish this by integrating whole brain functional MRI (fMRI) with psychophysical, physiological, and genotyping investigations. Many classical acupuncture points are proposed to have multiple regulatory functions and diverse clinical effects. If a common neural substrate subserves these multiple functions, it would require neural circuits that could modulate multiple physiological and neural systems. Given the rich diffusely projecting innervations of the monoamine neurotransmitter system, these neuromodulators, especially dopamine, may play an important early role in acupuncture action. Our overall hypothesis is that acupuncture will elicit a widespread brain response that is predominantly modulatory. The limbic system in particular, with its rich dopaminergic innervation, will play a central role. We will also explore the central neural substrate of deqi, a unique acupuncture sensation that is considered essential to clinical efficacy in traditional Chinese acupuncture. This Project will work with the other Project teams and the Neuroanatomy and Biostatistics Core to understand the neurobiology of acupuncture action and promote the development of this ancient healing technique into evidence-based medicine.